The peripheral chemoreceptors (carotid primarily, and the aortic bodies) detect changes in arterial blood oxygen and carbon dioxide, and initiate reflexes that are important for maintaining homeostasis during hypoxemia. The response to changing carbon dioxide (CO2) levels produces major changes in respiratory drive, of special importance to the control of ventilation during sleep. The carotid bodies are critical for ventilatory acclimatization to high altitude, and contribute in part to exercise-induced hyperventilation, and are critical for the generation of periodic breathing during sleep. Augmented peripheral chemoreflexes can contribute to the severity of sleep apnea, and the development of hypertension in sleep apnea syndromes. In congestive heart failure, augmented carotid chemoreflexes contributes to the increased sympathetic drive so typical of the disease. Moreover, this increase in chemoreflex gain is associated with increased mortality and periodic breathing during sleep, during exercise or even while resting wake. The term "chemoreflex-modulated sleep apnea" captures the whole spectrum of influence of the chemoreflexes on sleep-breathing. There is an unmet clinical need for the development of new therapeutic approaches for patients with chemoreflex-dependent or modulated sleep apnea, a problem especially prevalent in the congestive heart failure (CHF) population. There is currently no method to safely modulate the carotid chemoreflexes. Direct current (DC) electrical neural stimulation has a long history in experimental neurology. The carotid bodies in the neck are accessible to DC stimulation, which can both suppress or enhance neural activity. Peripheral chemoreflex excitatory (anodal) modulation could offer new treatment options for obesity hypoventilation and several neurological illnesses with insufficient central neural respiratory drive, and chronic mountain sickness, while inhibitory (cathodal) modulation could have a central role in management of central and chemoreflex modulated sleep apnea, certain forms of hypertension, high-altitude sleep fragmentation from periodic breathing, and allow safe reductions in the pathologically enhanced carotid chemoreflexes and sympathetic drive in heart failure. Transcervical DC stimulation may also be able to modulate the sensation of dyspnea in chronic obstructive lung disease. The long-term goal of this research is to develop a wearable device to safely and effectively modulate the carotid chemoreflexes. The applicants have already developed innovative new methods for phenotyping sleep apnea, and to use CO2 as adjunctive therapy for chemoreflex-modulated sleep apnea. The goal of the current Phase I SBIR proposal is to assess the safety (including adverse effects on the baroreflexes), acute physiological effects of cathodal and anodal transcervical DC stimulation in healthy volunteers, and exploratory effects on chemoreflex-modulated sleep apnea. PUBLIC HEALTH RELEVANCE: Narrative The carotid body in the neck is critical for regulating the normal amounts of oxygen and carbon dioxide in the blood in health and several disease states. There is currently no method to safely modulate carotid body activity. Direct Current (DC) stimulation can suppress or enhance activity of nervous tissue and using excitatory (anodal) DC current modulation could offer new treatment options for obesity hypoventilation and several neurological illnesses with insufficient central neural respiratory drive, and chronic mountain sickness, while inhibitory (cathodal) modulation could have a central role in management of central sleep apnea, certain forms of hypertension, poor sleep at high altitude, and allow safe reductions in the pathologically enhanced carotid body activity in heart failure. Transcervical DC stimulation may also be able to reduce the sensation of breathlessness in patients with chronic lung disease. The long-term goal of this research is to develop a wearable device to safely and effectively modulate the carotid chemoreflexes. The goal of the current proposal is to assess tolerance, safety, effects on breathing, and explore effects on central forms of sleep apnea.